Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non-Hodgkin lymphoma

Abstract

Bruton tyrosine kinase inhibitors (BTKi) have transformed the therapeutic landscape of chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma. However, primary and acquired resistance to BTKi can be seen due to a variety of mechanisms including tumour intrinsic and extrinsic mechanisms such as gene mutations, activation of bypass signalling pathways and tumour microenvironment. Herein, we provide an updated review of the key clinical data of BTKi treatment in CLL, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). We incorporate the most recent findings regarding mechanisms of resistance to covalent and non-covalent inhibitors, including ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib. We also cover the clinical sensitivity of certain molecular subtypes of DLBCL to an ibrutinib-containing regimen. Lastly, we summarise ongoing clinical investigations aimed at overcoming resistance via use of BTKi-containing combined therapies or the novel non-covalent BTKi. The review article targets an audience of clinical practitioners, clinical investigators and translational researchers.

Keywords: B-cell receptor (BCR); Bruton tyrosine kinase (BTK); chronic lymphocytic leukaemia (CLL); ibrutinib; non-Hodgkin lymphoma.

Fig. 1. Resistance-Relevant mutations and signaling pathways in CLL, MCL and DLBCL.

Key components of the signaling pathways including BCR, PI3K-AKT, MYD88/CD79, canonical NFκB and alternative NFκB are depicted. Mutated genes along these pathways associated with BTKi resistance are highlighted in yellow. Also see Table 4 for their relationship with the disease and resistance setting. Positive interactions are indicated by arrows, indirect interactions by dashed arrows, and inhibitory interactions by T-bars. The graph was generated with BioRender.

Fig.2.. Map of clinically documented BTK mutations.

A) 3D mapping of common BTK missense mutations associated with resistance to multiple BTK inhibitors (previously published in Sharma et al, PMID: 27626698). B) Clinically reported BTK mutations in patients treated with ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib. Note that not all mapped mutations have been functionally validated. PH, pleckstrin homology domain; TH, Tec homology domain; SH, Src homology domain; Tyrosine kinase, tyrosine kinase domain. The height of the vertical bars represents the relevant abundance of the particular variants. *Experimentally predicted to be resistant to multiple BTK inhibitors. The graph was generated with BioRender.